ABSTRACT Cystic fibrosis-related diabetes (CFRD) not only burdens affected patients with a second, attention-demanding disease but threatens nutritional status, pulmonary function, and survival. Developing strategies to preserve ?- cell function are crucial for interrupting CFRD development and its hazard to CF-relevant outcomes. The overall aims of this application are to better understand the initiation and progression of abnormal glucose tolerance in pancreatic insufficient CF (PI-CF) and to test a potential strategy for restoring ?-cell function. This application extends our recent studies demonstrating that 1) insulin secretion defects are present at glucose thresholds traditionally considered normal (one-hour oral glucose tolerance test [OGTT] glucose >155 but <200 mg/dL; referred to as early glucose intolerance [EGI]), 2) such subtle glucose abnormalities associate with increased CFRD risk and may portend greater declines in pulmonary function, and 3) infusion of incretin hormone, glucagon-like peptide-1 (GLP-1), but not glucose-dependent insulinotropic polypeptide (GIP), augments glucose- dependent insulin secretion in PI-CF. Our cross-sectional studies in CF demonstrate marked reductions in meal- related early-phase insulin secretion and ?-cell secretory capacity in EGI. With worsening glucose tolerance, PI- CF subjects with impaired glucose tolerance (IGT, two-hour OGTT glucose >140 but <200 mg/dL) and CFRD exhibit further compromised meal-related early-phase insulin secretion and ?-cell secretory capacity. The extent to which emergence and progression of glucose intolerance is a manifestation of worsening ?-cell secretory capacity is not known and will be investigated in longitudinal studies of youth and adults with PI-CF in whom mixed-meal tolerance tests (MMTT) will be performed to characterize early-phase insulin secretion and glucose- potentiated arginine (GPA) tests will be completed to quantify ?-cell secretory capacity. In Aim 1, we will leverage the genotyping and clinical phenotyping of our pediatric and adult CF cohort (n=350) to test the impact of T2D genetic variants, diet, CFTR modulator therapy, and pulmonary exacerbations on the emergence and progression of glucose intolerance and the relationship of glucose intolerance with nutritional status, pulmonary function, and body composition longitudinally over 3-5 years. In Aim 2 we will test whether our findings of ?-cell responsiveness to acute GLP-1 infusion has the potential to be translated into the use of chronic GLP-1 therapy as a mechanism to preserve ?-cell function. Specifically, we will pursue a proof-of-concept 6-week randomized, placebo-controlled cross-over study of the GLP-1 agonist, dulaglutide; the primary outcome will be the impact of dulaglutide upon meal-related early-phase insulin secretion, one of the earliest defects detected clinically. If successful, this work will provide the foundation for a multi-center study aimed at identifying and treating early insulin secretion defects in PI-CF and interrupting progression to CFRD.